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Low Density Lipoprotein Cholesterol and Coronary Heart Disease - Lower is Better
European Cardiology Review, 2005;1(1):1-6
Studies have consistently shown that coronary heart disease (CHD) risk is correlated closely with low density lipoprotein (LDL) cholesterol levels. The lower the LDL cholesterol, the lower the cardiovascular (CV) risk; however, there is a question over how much LDL cholesterol lowering is low enough and what supporting evidence there is for this. This article reviews recent evidence in support of the notion that ‘lower LDL cholesterol is better,’ drawing on revised guidelines from the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III). Data are presented to show that, in clinical practice, the majority of patients are treated suboptimally with traditional single inhibition statin monotherapy. In contrast, ezetimibe/simvastatin, a dual inhibitor of both cholesterol absorption and production, represents a more effective approach to treatment, allowing more patients to meet or exceed their LDL cholesterol goals.
Epidemiology has repeatedly shown that elevated levels of cholesterol play a key role in the development of atherosclerotic disease. In particular, low density lipoprotein (LDL) cholesterol has been strongly associated with coronary heart disease (CHD) risk.1–5 Lowering LDL cholesterol reduces the incidence of atherosclerotic disease, irrespective of how the reduction is achieved. The efficacy of statins in this respect is well-known,6 but similar improvements in CHD events can also be seen if a LDL cholesterol reduction is provided by cholestyramine and even surgical bypass.7–9 The message is clear and has been proven – lowering LDL cholesterol improves cardiovascular (CV) outcomes, irrespective of the mode; however, there is a question over how much LDL cholesterol lowering is low enough and what supporting evidence there is for this.
Statins, LDL Cholesterol and CHD Risk Reduction
Studies of statin usage in both primary and secondary prevention settings have shown consistently that the risk of a CHD event is correlated closely with LDL cholesterol levels (see Figure 1).7–10 The results are impressive. The benefits of lowering LDL cholesterol levels extend to men and women with widely differing CV risk profiles and include reductions in CHD and total mortality as well as myocardial infarction (MI), revascularisation procedures, stroke and peripheral vascular disease (PVD).11
- Pyörälä K, De Backer G, Graham I, Poole-Wilson P, Wood D, on behalf of the task force, “Prevention of coronary heart disease in clinical practice: recommendations of the Task Force of the European Society of Cardiology, European Atherosclerosis Society and European Society of Hypertension”, Eur. Heart J. (1994);15: pp. 1,300–1,331.
- “Executive summary of the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III)”, JAMA (2001);285: pp. 2,486–2,497.
- Stamler J, Wentworth D, Neaton J D, “Is the relationship between serum cholesterol and risk of premature death from coronary heart disease continuous and graded? Findings in 356,222 primary screenees of the Multiple Risk Factor Intervention Trial (MRFIT)”, JAMA (1986);256: pp. 2,823–2,828.
- Verschuren W M, Jacobs D R, Bloemberg B P et al., “Serum total cholesterol and long-term coronary heart disease mortality in different cultures: twenty-five-year follow-up of the Seven Countries Study”, JAMA (1995);274: pp. 131–136.
- Castelli W P, Anderson K, Wilson P W, Levy D, “Lipids and risk of coronary heart disease: the Framingham Study”, Ann. Epidemiol. (1992);2: pp. 23–28.
- Edwards J E, Moore R A, “Statins in hypercholesterolaemia: a dose-specific meta-analysis of lipid changes in randomised, double-blind trials”, BMC Family Practice (2003);4: p. 18. http://www.biomedcentral.com/1471-2296/4/18
- Buchwald H, Varco R L, Matts J P et al., “Effect of partial ileal bypass surgery on mortality and morbidity from coronary heart disease in patients with hypercholesterolemia. Report of the Program on the Surgical Control of the Hyperlipidemias (POSCH)”, N. Engl. J. Med. (1990):323: pp. 946–955.
- “The Lipid Research Clinics Coronary Primary Prevention Trial results I. Reduction in incidence of coronary heart disease”, JAMA (1984);251: pp. 351–364.
- “The Lipid Research Clinics Coronary Primary Prevention Trial results II. The relationship of reduction in incidence of coronary heart disease to cholesterol lowering”, JAMA (1984);251: pp. 365–374.
- O’Keefe J H, Cordain L, Harris W H, Moe R M, Vogel R, “Optimal low-density lipoprotein is 50 to 70 mg/dl. Lower is better and physiologically normal”, J. Am. Coll. Cardiol. (2004);43: pp. 2,142–2,146.
- Pasternak R C, Smith S C, Bairey-Merz C N, Grundy S M, Cleeman J I, Lenfant C “ACC/AHA/NHLBI clinical advisory on the use and safety of statins”, Circulation (2002);106: pp. 1,024–1,028.
- Nissen S E, Tuzcu E M, Schoenhagen P et al., for the REVERSAL investigators, “Effect of intensive compared with moderate lipid-lowering therapy on progression of coronary atherosclerosis”, JAMA (2004);291: pp. 1,071–1,080.
- Smilde T J, van Wissen S, Wollersheim H, Trip M D, Kastelein J J P, Stalenhoef A F H, “Effect of aggressive versus conventional lipid lowering on atherosclerosis progression in familial hypercholesterolemia (ASAP): a prospective, randomised, double-blind trial”, Lancet (2001);357: pp. 577–581.
- Taylor A J, Kent S M, Flaherty P J, Coyle L C, Markwood T T, Vernalis M N, “ARBITER: Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol: a randomized trial comparing the effects of atorvastatin and pravastatin on carotid intima medial thickness”, Circulation (2002);106: pp. 2,055–2,060.
- Cannon C P, Braunwald E, McCabe C H et al., for the pravastatin or atorvastatin evaluation and infection therapy – Thrombolysis in Myocardial Infarction 22 Investigators, “Intensive versus moderate lipid lowering with statins after acute coronary syndromes”, N. Engl. J. Med. (2004);350: pp. 1,495–1,504.
- Tamai O, Hidehiro M, Itabe H, Wada Y, Kohno K, Imaizumi T, “Single LDL apheresis improves endotheliumdependent vasodilatation in hypercholesterolemic humans”, Circulation (1997);95: pp. 76–82.
- LaRosa J C, Grundy S M, Waters D D et al., for the Treating to New Targets (TNT) Investigators, N. Engl. J. Med. (8 March 2005);352:(e-pub).
- Grundy S M, Cleeman J I, Bairey Merz C N et al., for the Coordinating Committee of the National Cholesterol Education Program, J. Am. Coll. Cardiol. (2004);44: pp. 720–732.
- Heart Protection Collaborative Group, “MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20 536 high-risk individuals: a randomised placebo-controlled trial”, Lancet (2002);360: pp. 7–22.
- Shepherd J, Blauw GJ, Murphy MB et al., on behalf of the PROSPER study group, “Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial. Prospective Study of Pravastatin in the Elderly at Risk”, Lancet (2002);360: pp. 1,623–1,630.
- ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group, “The Antihypertensive and Lipid- Lowering Treatment to Prevent Heart Attack Trial. Major outcomes in moderately hypercholesterolemic, hypertensive patients randomized to pravastatin vs usual care: the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT-LLT)”, JAMA (2002);288: pp. 2,998–3,007.
- Sever P S, Dahlöf B, Poulter N R et al., for the ASCOT investigators, “Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo- Scandinavian Cardiac Outcomes Trial – Lipid Lowering Arm (ASCOT-LLA): a multicentre randomised controlled trial”, Lancet (2003);361: pp. 1,149–1,158.
- De Backer G, Abrosioni E, Borch-Johnsen K et al., “European Guidelines on cardiovascular disease prevention in clinical practice. Third Joint Task Force of European and other Societies on Cardiovascular Disease Prevention in Clinical Practice”, Eur. Heart J. (2003);24: pp. 1,601–1,610.
- Euroaspire I and II Group, “Clinical reality of coronary prevention guidelines: a comparison of EUROASPIRE I and II in nine countries”, Lancet (2001);357: pp. 995–1,001.
- Pearson T A, “The Lipid Treatment Assessment Project (L-TAP): a multicenter survey to evaluate the percentages of dyslipidemic patients receiving lipid-lowering therapy and achieving low-density lipoprotein goals”, Arch. Intern. Med. (2000);160: pp. 459–467.
- García Ruiz F J, Marín Ibáñez A, Pérez Jiménez F, Pintó X, Nocea G, Ahumada C, Alemao E, Yin D, REALITY Study Group, “Current lipid management and low cholesterol goal attainment in common daily practice in Spain. The REALITY Study”, Pharmacoeconomics (2004); 22 (suppl 3): pp. 1–12.
- Goettsch W G, Yin D D, Alemao E, Klungel O H, Stalenhoef A F, Herings R M C, “Statins are less effective in common daily practice among patients with hypercholesterolemia: the REALITY-PHARMO study”, Curr. Med. Res. Opin. (2004);20: pp. 1,025–1,033.
- Krobot K J, Yin D D, Alemao E, Steinhagen-Thiessen E, “Real-world effectiveness of lipid-lowering therapy in male and female outpatients with CHD: relation to pre-treatment LDL-cholesterol, pre-treatment CHD risk, and other factors”, Eur. J. Cardiovasc. Prev. Rehabil. (2005);12: pp. 37–45.
- Lindgren P, Borgström F, Stålhammar, Alemao E, DonpingYin D, Jönsson L, “Association between achieving treatment goals for lipid-lowering and cardiovascular events in real clinical practice”, Eur. J. Cardiovasc. Prev. Rehabil. (2005) (in press).
- Knopp R H, “Drug treatment of lipid disorders”, New Engl. J. Med. (1999);341: pp. 498–511.
- De Lemos J A, Blazing M A, Wiviott S D et al., for the A to Z Investigators, “Early intensive vs a delayed conservative simvastatin strategy in patients with acute coronary syndromes. Phase Z of the A to Z trial”, JAMA (2004);292; pp. 1,307–1,316.
- Leiter L A, Betteridge D J, the AUDIT investigators, “The AUDIT Study: A worldwide survey of physician attitudes about diabetic dyslipidemia”, presented at the 64th Annual Scientific Sessions of the American Diabetes Association (June 6 2004); Orlando, FL, US. http://www.pslgroup.com/dg/24452a.htm
- Feldman T, Koren M, Insull W Jr et al., “Treatment of high-risk patients with ezetimibe plus simvastatin co-administration versus simvastatin alone to attain National Cholesterol Education Program Adult Treatment Panel III low-density lipoprotein cholesterol goals”, Am. J. Cardiol. (2004);93: pp. 1,481–1,486.
- Ballantyne C M, Blazing M A, King T R, Brady W E, Palmisano J, “Efficacy and safety of ezetimibe co-administered with simvastatin compared with atorvastatin in adults with hypercholesterolemia”, Am. J. Cardiol. (2004);93: pp. 1,487–1,494.
- Goldberg A C, Sapre A, Liu J, Capece R, Mitchel Y B, for the Ezetimibe Study Group, “Efficacy and safety of ezetimibe coadministered with simvastatin in patients with primary hypercholesterolemia: a randomized, double-blind, placebocontrolled trial”, Mayo Clin. Proc. (2004);79: pp. 620–629.
- Davidson M H, McGarry T, Bettis R, Melani L, Lipka L J, LeBaut A P, Suresh R, Sun S, Veltri E P, on behalf of the Ezetimibe Study Group, “Ezetimibe coadministered with simvastatin in patients with primary hypercholesterolemia”, J. Am. Coll. Cardiol. (2002);40: pp. 2,125–2,134.
- Gaudiani L M, Lewin A, Meneghini L, Pervozskaya I, Plotkin D, Mitchel Y, Shah S, “Efficacy and safety of ezetimibe co-administered with simvastatin in thiazolidinedione-treated type 2 diabetic patients”, Diab. Obes. Metab. (2005);7: pp. 88–97.
- Ballantyne C M, Abate N, Yuan Z, King T, Palmisano J, “Attainment of optimal National Cholesterol Education Program Adult Treatment Panel III treatment goals in high risk patients: dose comparison of Vytorin (ezetimibe/simvastatin) and atorvastatin”, poster (#1129–111) presented at the annual meeting of the American College of Cardiology (6–9 March 2005), Orlando, FL, US.